The application is for the continued support of a Program Project Grant in one of the twelve Retardation Centers initially funded under PL 88-164. It is composed of three projects which have as their primary goal to better understand enzyme mechanisms and/or biochemical defects relevant to a number of closely related genetic disorders which can result in mental retardation and/or early death. These disorders involve inherited defects of glutaryl-CoA dehydrogenase, general (medium-chain) acyl-CoA dehydrogenase (GAD), electron transfer flavoprotein (ETF) and ETF:ubiquinone oxidoreductase (ETF:QO) (the two proteins which transfer electrons from primary flavoprotein dehydrogenases to Complex III of the main respiratory chain), and of Complex III itself. The three BF Stolinsky investigators are linked through their common goals, constant interaction, exchange of methods and equipment, and their use of common tissue culture and recombinant DNA facilities. The fourth investigator, Dr. Neil Howell, at the University of Texas in Galveston, has been working with us for several months and brings longstanding expertise and interest in respiratory chain diseases to the project. Project 1 is concerned with glutaric acidemia, a disorder which causes mental retardation and degeneration of the basal ganglia, and will examine functional domains of normal glutaryl-coenzyme A dehydrogenase as well as how normal function is perturbed by naturally occurring mutations. Project 2 focuses on GAD deficiency and glutaric acidemia type II (GA2), disorders which cause early death as well as (in GA2) congenital anomalies, and will seek to identify functional domains of GAD and to investigate bimolecular complexes between GAD and ETF, and between ETF and ETF:QO. Project 3 will seek to identify mutations in patients with apparent defects in Complex III, and initial studies will focus on a family in which biochemical evidence strongly suggests a primary defect in cytochrome b, a mitochondrially encoded protein. All of these projects have the common goal of eventually understanding how disturbed enzyme function leads to disease, since only with such information can rational approaches to therapy be developed.